Control of airway inflammation and Th2 differentiation by microRNA 21

microRNA 控制气道炎症和 Th2 分化 21

• 批准号: 8434965
• 负责人: Alexander L Dent
• 金额: $ 19.3万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434965
• 关键词: Address; Affect; Allergic Disease; Allergic inflammation; Area; Asthma; Atopic Dermatitis; BCL6 gene; Binding Sites; CD4 Positive T Lymphocytes; Cell Differentiation process; Conjunctivitis; Disease; Food Hypersensitivity; GATA3 transcription factor; Gene Expression; Generations; Genes; Genetic Transcription; Hypersensitivity; Immune system; Incidence; Inflammation; Inflammatory; Interleukin-4; Investigation; Lead; Lung; Malignant Neoplasms; Maps; Mediating; MicroRNAs; Molecular; Pathologic; Pathway interactions; Phosphotransferases; Production; Regulation; Regulator Genes; Relative (related person); Repression; Role; STAT3 gene; Signal Transduction; Sinusitis; T-Lymphocyte; Testing; Th2 Cells; Up-Regulation; Urban Population; airway inflammation; allergic airway inflammation; atopy; cell type; cytokine; in vivo; insight; mouse model; novel; novel diagnostics; promoter; protein expression; research study

DESCRIPTION (provided by applicant): The incidence of Th2 cell-mediated atopic and allergic diseases are increasing dramatically worldwide, with almost 50% of the urban population presenting with atopic diseases including asthma, rhino- conjunctivitis, sinusitis, food allergy, and atopic dermatitis. Thus, new diagnostic markers and treatments for allergic diseases remain a high priority. Micro-RNAs (miRs) are important regulators of gene expression, and in particular, miRs critically control immune system function. MiRs are deregulated in many pathologic conditions, and miRs have been studied extensively in cancer and the inflammation associated with cancer. The role of miRs in other types of inflammation is a relatively new area of investigation, and little is known about miRs in allergic disease and allergic inflammation. MiR21 was found to be highly up-regulated in lungs with Th2-type allergic inflammation, and we recently have found that more severe allergic inflammation in the lung correlates with strongly increased miR21 expression. We have further established that increased miR21 expression in T cells can promote Th2 differentiation. Thus, we hypothesize that during inflammatory conditions, high miR21 expression promotes further inflammation and amplified Th2 differentiation. This hypothesis predicts that blocking miR21 can alleviate Th2-type inflammation, and in this proposal we will test miR21 inhibition as a potential therapy for allergic disease. We will further define the role of miR21 in Th2 differentiation and inflammation, by elucidating the mechanism by which miR21 promotes Th2 differentiation. We will also analyze what specific cell types up-regulate miR21 during inflammation. MiR21 transcription is induced by activated STAT3, and we have determined that miR21 transcription is repressed by BCL6. We will explore the relationship of BCL6 repression of miR21 to activation by STAT3, and if there is an antagonistic regulation of miR21 by STAT3 and BCL6 that controls Th2 differentiation. These studies have the potential to lead to new treatments for allergic disease, as well as provide novel insights into the pathogenic mechanisms of allergy and atopy.

描述(申请人提供)：Th2细胞介导的特应性和过敏性疾病的发病率在全球范围内急剧增加，近50%的城市人口出现特应性疾病，包括哮喘、鼻结膜炎、鼻窦炎、食物过敏和特应性皮炎。因此，过敏性疾病的新诊断标记物和治疗方法仍然是一个高度优先的问题。Micro-RNAs(MiRs)是基因表达的重要调节因子，尤其是miRs对免疫系统的功能起着至关重要的控制作用。在许多病理条件下，MIR被解除调控，并且MIR在癌症和与癌症相关的炎症中得到了广泛的研究。MIR在其他类型炎症中的作用是一个相对较新的研究领域，对MIR在变态反应性疾病和过敏性炎症中的作用知之甚少。在患有Th2型变态反应性炎症的肺部，miR21被发现高度上调，我们最近发现，肺中更严重的变态反应性炎症与miR21表达的强烈增加相关。我们进一步证实，增加T细胞miR21的表达可以促进Th2的分化。因此，我们假设在炎症条件下，miR21的高表达促进进一步的炎症并放大Th2分化。这一假设预测，阻断miR21可以缓解Th2型炎症，在这项建议中，我们将测试miR21抑制作为变态反应性疾病的潜在治疗方法。我们将通过阐明miR21促进Th2分化的机制，进一步明确miR21在Th2分化和炎症中的作用。我们还将分析哪些特定类型的细胞在炎症过程中上调miR21。MiR21的转录是由激活的STAT3诱导的，我们已经确定miR21的转录被BCL6抑制。我们将探讨BCL6对miR21的抑制与STAT3激活的关系，以及是否存在STAT3和BCL6对miR21的拮抗调节，从而控制Th2分化。这些研究有可能为过敏性疾病带来新的治疗方法，并为过敏和特应性反应的发病机制提供新的见解。